Project Summary (Overall) This renewal application stems from our successful first four years of a new program project grant funded in 2011, which brings together a talented group of investigators with expertise in basic biology (DFCI and Whitehead Institute at MIT), clinical science (IFM), as well as genomic and cell signaling (Sanger Institute UK and DFCI). During the prior 4 years of funding period, we have 1. defined the role of transplant in the era of novel agents; 2 Established the role of molecular minimal residual disease (MRD) in myeloma. 3. Established the role of both MRI and PET/CT in diagnosis and follow up of MM patients. 4. Identified and Validated number of novel targets. and 5. Defined patterns of clonal evolution and mutational signatures being utilized in MM. Our program has also developed novel targeted sequencing platform, developed a pipeline to identify mutations using RNA-seq, and developed a publicly available data analysis portal (Canevolve.org). Building on these advances, The overall specific objectives of the program are 1) To determine whether maintenance can be tailored based upon MRD status and whether achieving MRD negative status provides superior outcome In a 1260 patient randomized clinical study and to develop novel risk model (Project 1). Clinically annotated patient samples from this clinical trial will be utilized to study genomic and epigenomic correlates; 2) To identify the spectrum of epigenomic lesions and enhancer dependencies that underlie pathogenesis, progression, and clinical outcome in MM. (Project 2). New clinically-relevant epigenomic-centered targets identified will be validated further; 3) To identify and validate the molecular circuits/loops responsible for continued MM cell growth and develop strategies to interrupt these loops as a novel therapeutic approach. (Project 3). New targeted therapeutic agents will be translated to clinical trials to improve patient outcome; and 4) To define the impact of therapy on clonal evolution and identify mediators of genomic instability underlying disease prognosis and progression in MM (Project 4). New clinically relevant processes identified will be used to understand process of progression. These 4 projects will be supported by Administrative and Communication Core (1), Clinical and Tissue Core (2); Genomics Core (3); Genomic Sequencing Core (4) and Biostatistical and Bioinformatics Cores (5). This unique collaborative effort will improve our understanding of myeloma biology and define a new treatment paradigm for this presently incurable disease.